Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands an... more Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymatic elements involved in their synthesis and breakdown. Aim. To report on currently held knowledge about the functioning of the system as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis. Development. Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammation and neural damage. In this context then, their actions in the microglial cells and in the astrocytes are characterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore, cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models of multiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. Conclusions. The clinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammation of the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailed analysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms of action of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation. Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool.
Several data suggest that the limbic structures in general and the amygdala in particular may be ... more Several data suggest that the limbic structures in general and the amygdala in particular may be involved in the regulation of LH and FSH secretion. On the basis of lesion and stimulation experiments, it has been postulated that, in adult animals, the amygdala may exert either stimulatory or inhibitory influences on gonadotropin release (for references, see: Schiaffini and Martini, 1972; Smith and Lawton, 1972; Kawakami and Terasawa, 1972; Karakami et al., 1973; Ellendorf et al., 1973; Kanematsu et al., 1974). A participation of the amygdala in the development of puberty has also been suggested (Critchlcw and Bar-Sela, 1967), but this has been denied by others (Bloch and Ganong, 1971; Relkin, 1971 a and b). In addition, the hypothesis has been put forward that the amygdala might participate in the feedback mechanisms through which sex steroids control LH and FSH output (for references, see: Piva et al., 1973; McEwen and Pfaff, 1973; Terasawa and Kawakami, 1974; Parvizi and Ellendorf, 1975). Finally, it has been reported that the oxydative metabolism of the amygdala may be influenced by castration as well as by the administration of sex steroids and of anterior pituitary hormones (Schiaffini and Martini, 1972).
Our findings on the effects of trilostane (T) on adrenal lie-hydroxysteroid dehydrogenase (IIB-HS... more Our findings on the effects of trilostane (T) on adrenal lie-hydroxysteroid dehydrogenase (IIB-HSD) in vitro (Touitou et al JSB 20, 763-768, 1984) led us to look for a possible similar action of aminoglutethimide (AG) and metyrapone (M). Sheep adrenals were incubated with tritiated II-deoxycortisol (S), cortisol (F) or IIB-hydroxyandroetenedione (11A4) at 37' C for 2 hours in the presence of AG, M and T. An apparent dramatic inhibition (86-99 X) of F synthesis from S was observed with the 3 drugs, but cortisone (E) synthesis (II@HSD activity) reached 54 % (AG), 42 % (T) and 1.5 Z CM). Thus, the inhibition of 118-hydroxylase (IlB-OHare) computed with 11 oxosteroids (F + E) was actually 20 X (AG), 24 X (T) and 98 X (M). Incubations with F and 11A1, as precursors confirmed the effects of the drugs on IIB-HSD (conversion to E and adrenoeterone respectively). Incubations 'without adrenal tissue showed that the drugs had no direct oxydatLve iffects. This work shows that inhibitors of adrenal steroidogenesis can also induce an enhanced
The Spanish government created in 1902 a research laboratory for Cajal, 1906 Nobel Prize and foun... more The Spanish government created in 1902 a research laboratory for Cajal, 1906 Nobel Prize and founder of modern neuroscience. The laboratory was translated, enlarged and renamed as Instituto Cajal in 1993 and incorporated to the CSIC in 1939. The excessive morphological specialization of the institute and the explosion of neuroscience as a multidisciplinary discipline were the conditions for a radical renovation initiated in 1985 under the auspices of the presidency of the CSIC and following the recommendations of several international advisory boards. The transformation of the Cajal Institute in a competitive multidisciplinary research centre culminated in 1989, with the inauguration of new facilities in its present location. As a result of the extreme success of this transformation the Cajal Institute has now grown to unpredicted dimensions of infrastructure and personnel that demand a new physical location to allow for its continuous growth as a leading European center in neuroscience research.Peer Reviewe
Products derived from the activated immune system have been reported to modulate neuroendocrine f... more Products derived from the activated immune system have been reported to modulate neuroendocrine function. In addition, a direct connection between neuroendocrine and immune responses to stress has recently been proposed. We now provide evidence that heterogeneous lymphokine-containing supernatants from mitogen-stimulated rat spleen cells can stimulate both basal and corticotropin-induced corticosterone secretion from rat adrenal cells in an in vitro perifusion system. Moreover, thymosin alpha 1, a 28-amino acid residue peptide found both in thymus and lymphocyte-derived supernatants was also able to synergistically stimulate corticotropin-stimulated corticosterone release, without affecting basal corticosterone output in this same in vitro adrenal cell perifusion system. These results reinforce the suggestion about the existence of bidirectional interactions between the immune and neuroendocrine systems. They also indicate that this communication may occur directly at the adrenal gland level, a major effector site of the body's response to stress.
for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period ... more for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period took a 1.2 g daily dose of Sevitin (basic group) for 30 days, and the other 14 alcoholic patients were not given any medication treatment during the rehabilitation period (comparison group). Clinical dynamic of basic signs of the alcoholic patients pathological addiction to alcohol (affective, neurovegetative, ideator, dissomnic and behavioral) was rated in scores. The scores were self-reported by patients twice: first e before the rehabilitative period and second e after 30 days of rehabilitation.
for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period ... more for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period took a 1.2 g daily dose of Sevitin (basic group) for 30 days, and the other 14 alcoholic patients were not given any medication treatment during the rehabilitation period (comparison group). Clinical dynamic of basic signs of the alcoholic patients pathological addiction to alcohol (affective, neurovegetative, ideator, dissomnic and behavioral) was rated in scores. The scores were self-reported by patients twice: first e before the rehabilitative period and second e after 30 days of rehabilitation.
Drugs able to mimic or to antagonize the action of catecholamines have been implanted bilaterally... more Drugs able to mimic or to antagonize the action of catecholamines have been implanted bilaterally into the basomedial region of the amygdala of adult castrated female rats. The animals were killed at different intervals after the implantation of the different drugs, and serum levels of LH and FSH were measured by radioimmunoassay. The results have shown that the intra-amygdalar implantation of the alpha-adrenergic blocker phenoxybenzamine induces a significant increase of the release both of LH and FSH. The implantation of the beta-adrenergic blocker propranolol brings about a rise of LH only. The dopamine receptor blocker pimozide stimulates the release of LH and exerts a biphasic effect (stimulation followed by inhibition) of FSH secretion. The alpha-receptor stimulant clonidine and the dopaminergic drug 2-Br-alpha-ergocryptine were without significant effects. From these observations it is suggested that the adrenergic signals reaching the basomedial area of the amygdala (possibl...
Experiments have been performed to study the role of the amygdala and of the organum uasculosum l... more Experiments have been performed to study the role of the amygdala and of the organum uasculosum laminue terminalis (OVLT) in the control of gonadotrophin secretion. Amygdala. Drugs known as antagonists or agonists of the adrenergic and of the cholinergic receptors have been implanted at the level of the basomedial area of the amygdala in long-term castrated female rats. The animals were sacrificed at different time intervals after implantation, and their serum levels of LH and FSH were measured with specific radioimmunoassays and compared to those of shamimplanted animals. The results have shown that adrenergic and cholinergic receptors involved in the control of gonadotrophin secretion are present in the amygdala. In particular, the data have shown that: (1) a-adrenergic receptors of the amygdala exert an inhibitory tone on LH and FSH secretion; (2) I-adrenergic receptors seem to exert an inhibitory influence only on LH release; (3) cholinergic receptors of the muscarinic type appear to exert an inhibitory influence on LH output; (4) cholinergic receptors of the nicotinic type seem to play a role in depressing FSH secretion. OVLT. This structure was destroyed by radiofrequency lesions in regularly cycling and in long-term castrated adult female rats. After OVLT lesion practically all cycling .femJes (16 out of 22) entered a dioestrous status, as indicated by vaginal smears. At the moment of sacrifiy (8 days after the lesion) their serum gonadotrophin levels were as low as those present in cycling animals in the phase of dioestrus. Castrated females bearing OVLT lesions had serum titres of LH and FSH as high as those of castrated controls. It is concluded that the OVLT plays a role in the control of the "cyclic" release of gonadotrophins, but is not involved in the "tonic" regulation of gonadotrophin secretion. This paper summarizes the data of two groups of experiments performed in this laboratory on the participation of the amygdala and of the organum vasculosum laminae terminalis (OVLT) in the control of gonadotrophin secretion and of ovarian function in the female rat.
The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF)... more The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF) and lipopolysaccharide (LPS) on hippocampal corticosteroid receptors were studied in the rat. Type I (mineralocorticoid) and type II (glucocorticoid) receptors were measured in hippocampal cytosolic fractions with the radioligand binding technique, using 3H-corticosterone and 3H-RU 28362, respectively. LPS, administered intraperitoneally (50 micrograms/kg 8 h before sacrifice or 100 micrograms/kg injected twice, 16 and 8 h before sacrifice) to rats which had been previously adrenalectomized to allow for clearance of endogenous corticosterone, did not modify either type of corticosteroid receptors in the hippocampus. IL-1, IL-6, TNF or saline were injected intracerebroventricularly (50 ng/rat) and the animals were killed 3 h after. Type I receptors were not affected by any of the cytokines studied. Moreover, no changes in type II receptors were observed after IL-1 or IL-6 administration. In contrast, hippocampal type II receptors were dramatically decreased after the injection of TNF. The TNF-induced downregulation of type II receptors was secondary to a marked decrease in the affinity of the receptors (Kd increased 7.2-fold), accompanied by a 51% decrease in receptor number (Bmax). These results emphasize the important role played by TNF in the modulation of the hypothalamic-pituitary-adrenal axis during immune/inflammatory processes and extend the central sites of action of this cytokine to the corticosteroid receptors of the hippocampus.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Nov 1, 1988
Possible modulatory effects of psychoneurogenic stress and endotoxin-induced immune activation on... more Possible modulatory effects of psychoneurogenic stress and endotoxin-induced immune activation on the in vitro corticosterone-releasing effects of lymphokine-containing supernatants (LCS) and adrenocorticotropic hormone (ACTH) were studied in rats. We have found that activation of the immune system by endotoxin increases the in vitro sensitivity of the adrenocortical cells to LCS and ACTH. In addition, we found that psychoneurogenic stress not only produced an increase of in vitro adrenal sensitivity to ACTH, but it also enhanced the release of corticosterone after perfusion of LCS. A synergistic interaction between ACTH and LCS was observed in all experimental groups of animals studied. An increased adrenal sensitivity to LCS and ACTH after stress or immune activation might have a functional significance, since the adrenal cortex is a major site in the response of the organism to alterations in the homeostatic balance. On the other hand, the temporal pattern of in vitro corticosterone release after LCS was different in all groups under study compared with that observed after ACTH challenge. LCS elicited a more rapid corticosterone response that lasted for a shorter time than after giving ACTH. These latter results suggest that different mechanisms may underlie the effects of LCS and ACTH on adrenal corticosteroidogenesis. In conclusion, the present findings further reinforce the existence of possible physiologically relevant interactions between the immune system and the pituitary-adrenal axis.
Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands an... more Introduction. The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymatic elements involved in their synthesis and breakdown. Aim. To report on currently held knowledge about the functioning of the system as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis. Development. Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammation and neural damage. In this context then, their actions in the microglial cells and in the astrocytes are characterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore, cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models of multiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. Conclusions. The clinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammation of the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailed analysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms of action of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation. Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool.
Several data suggest that the limbic structures in general and the amygdala in particular may be ... more Several data suggest that the limbic structures in general and the amygdala in particular may be involved in the regulation of LH and FSH secretion. On the basis of lesion and stimulation experiments, it has been postulated that, in adult animals, the amygdala may exert either stimulatory or inhibitory influences on gonadotropin release (for references, see: Schiaffini and Martini, 1972; Smith and Lawton, 1972; Kawakami and Terasawa, 1972; Karakami et al., 1973; Ellendorf et al., 1973; Kanematsu et al., 1974). A participation of the amygdala in the development of puberty has also been suggested (Critchlcw and Bar-Sela, 1967), but this has been denied by others (Bloch and Ganong, 1971; Relkin, 1971 a and b). In addition, the hypothesis has been put forward that the amygdala might participate in the feedback mechanisms through which sex steroids control LH and FSH output (for references, see: Piva et al., 1973; McEwen and Pfaff, 1973; Terasawa and Kawakami, 1974; Parvizi and Ellendorf, 1975). Finally, it has been reported that the oxydative metabolism of the amygdala may be influenced by castration as well as by the administration of sex steroids and of anterior pituitary hormones (Schiaffini and Martini, 1972).
Our findings on the effects of trilostane (T) on adrenal lie-hydroxysteroid dehydrogenase (IIB-HS... more Our findings on the effects of trilostane (T) on adrenal lie-hydroxysteroid dehydrogenase (IIB-HSD) in vitro (Touitou et al JSB 20, 763-768, 1984) led us to look for a possible similar action of aminoglutethimide (AG) and metyrapone (M). Sheep adrenals were incubated with tritiated II-deoxycortisol (S), cortisol (F) or IIB-hydroxyandroetenedione (11A4) at 37' C for 2 hours in the presence of AG, M and T. An apparent dramatic inhibition (86-99 X) of F synthesis from S was observed with the 3 drugs, but cortisone (E) synthesis (II@HSD activity) reached 54 % (AG), 42 % (T) and 1.5 Z CM). Thus, the inhibition of 118-hydroxylase (IlB-OHare) computed with 11 oxosteroids (F + E) was actually 20 X (AG), 24 X (T) and 98 X (M). Incubations with F and 11A1, as precursors confirmed the effects of the drugs on IIB-HSD (conversion to E and adrenoeterone respectively). Incubations 'without adrenal tissue showed that the drugs had no direct oxydatLve iffects. This work shows that inhibitors of adrenal steroidogenesis can also induce an enhanced
The Spanish government created in 1902 a research laboratory for Cajal, 1906 Nobel Prize and foun... more The Spanish government created in 1902 a research laboratory for Cajal, 1906 Nobel Prize and founder of modern neuroscience. The laboratory was translated, enlarged and renamed as Instituto Cajal in 1993 and incorporated to the CSIC in 1939. The excessive morphological specialization of the institute and the explosion of neuroscience as a multidisciplinary discipline were the conditions for a radical renovation initiated in 1985 under the auspices of the presidency of the CSIC and following the recommendations of several international advisory boards. The transformation of the Cajal Institute in a competitive multidisciplinary research centre culminated in 1989, with the inauguration of new facilities in its present location. As a result of the extreme success of this transformation the Cajal Institute has now grown to unpredicted dimensions of infrastructure and personnel that demand a new physical location to allow for its continuous growth as a leading European center in neuroscience research.Peer Reviewe
Products derived from the activated immune system have been reported to modulate neuroendocrine f... more Products derived from the activated immune system have been reported to modulate neuroendocrine function. In addition, a direct connection between neuroendocrine and immune responses to stress has recently been proposed. We now provide evidence that heterogeneous lymphokine-containing supernatants from mitogen-stimulated rat spleen cells can stimulate both basal and corticotropin-induced corticosterone secretion from rat adrenal cells in an in vitro perifusion system. Moreover, thymosin alpha 1, a 28-amino acid residue peptide found both in thymus and lymphocyte-derived supernatants was also able to synergistically stimulate corticotropin-stimulated corticosterone release, without affecting basal corticosterone output in this same in vitro adrenal cell perifusion system. These results reinforce the suggestion about the existence of bidirectional interactions between the immune and neuroendocrine systems. They also indicate that this communication may occur directly at the adrenal gland level, a major effector site of the body's response to stress.
for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period ... more for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period took a 1.2 g daily dose of Sevitin (basic group) for 30 days, and the other 14 alcoholic patients were not given any medication treatment during the rehabilitation period (comparison group). Clinical dynamic of basic signs of the alcoholic patients pathological addiction to alcohol (affective, neurovegetative, ideator, dissomnic and behavioral) was rated in scores. The scores were self-reported by patients twice: first e before the rehabilitative period and second e after 30 days of rehabilitation.
for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period ... more for one month, were subjects in the research. 32 alcoholic patients in the rehabilitation period took a 1.2 g daily dose of Sevitin (basic group) for 30 days, and the other 14 alcoholic patients were not given any medication treatment during the rehabilitation period (comparison group). Clinical dynamic of basic signs of the alcoholic patients pathological addiction to alcohol (affective, neurovegetative, ideator, dissomnic and behavioral) was rated in scores. The scores were self-reported by patients twice: first e before the rehabilitative period and second e after 30 days of rehabilitation.
Drugs able to mimic or to antagonize the action of catecholamines have been implanted bilaterally... more Drugs able to mimic or to antagonize the action of catecholamines have been implanted bilaterally into the basomedial region of the amygdala of adult castrated female rats. The animals were killed at different intervals after the implantation of the different drugs, and serum levels of LH and FSH were measured by radioimmunoassay. The results have shown that the intra-amygdalar implantation of the alpha-adrenergic blocker phenoxybenzamine induces a significant increase of the release both of LH and FSH. The implantation of the beta-adrenergic blocker propranolol brings about a rise of LH only. The dopamine receptor blocker pimozide stimulates the release of LH and exerts a biphasic effect (stimulation followed by inhibition) of FSH secretion. The alpha-receptor stimulant clonidine and the dopaminergic drug 2-Br-alpha-ergocryptine were without significant effects. From these observations it is suggested that the adrenergic signals reaching the basomedial area of the amygdala (possibl...
Experiments have been performed to study the role of the amygdala and of the organum uasculosum l... more Experiments have been performed to study the role of the amygdala and of the organum uasculosum laminue terminalis (OVLT) in the control of gonadotrophin secretion. Amygdala. Drugs known as antagonists or agonists of the adrenergic and of the cholinergic receptors have been implanted at the level of the basomedial area of the amygdala in long-term castrated female rats. The animals were sacrificed at different time intervals after implantation, and their serum levels of LH and FSH were measured with specific radioimmunoassays and compared to those of shamimplanted animals. The results have shown that adrenergic and cholinergic receptors involved in the control of gonadotrophin secretion are present in the amygdala. In particular, the data have shown that: (1) a-adrenergic receptors of the amygdala exert an inhibitory tone on LH and FSH secretion; (2) I-adrenergic receptors seem to exert an inhibitory influence only on LH release; (3) cholinergic receptors of the muscarinic type appear to exert an inhibitory influence on LH output; (4) cholinergic receptors of the nicotinic type seem to play a role in depressing FSH secretion. OVLT. This structure was destroyed by radiofrequency lesions in regularly cycling and in long-term castrated adult female rats. After OVLT lesion practically all cycling .femJes (16 out of 22) entered a dioestrous status, as indicated by vaginal smears. At the moment of sacrifiy (8 days after the lesion) their serum gonadotrophin levels were as low as those present in cycling animals in the phase of dioestrus. Castrated females bearing OVLT lesions had serum titres of LH and FSH as high as those of castrated controls. It is concluded that the OVLT plays a role in the control of the "cyclic" release of gonadotrophins, but is not involved in the "tonic" regulation of gonadotrophin secretion. This paper summarizes the data of two groups of experiments performed in this laboratory on the participation of the amygdala and of the organum vasculosum laminae terminalis (OVLT) in the control of gonadotrophin secretion and of ovarian function in the female rat.
The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF)... more The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF) and lipopolysaccharide (LPS) on hippocampal corticosteroid receptors were studied in the rat. Type I (mineralocorticoid) and type II (glucocorticoid) receptors were measured in hippocampal cytosolic fractions with the radioligand binding technique, using 3H-corticosterone and 3H-RU 28362, respectively. LPS, administered intraperitoneally (50 micrograms/kg 8 h before sacrifice or 100 micrograms/kg injected twice, 16 and 8 h before sacrifice) to rats which had been previously adrenalectomized to allow for clearance of endogenous corticosterone, did not modify either type of corticosteroid receptors in the hippocampus. IL-1, IL-6, TNF or saline were injected intracerebroventricularly (50 ng/rat) and the animals were killed 3 h after. Type I receptors were not affected by any of the cytokines studied. Moreover, no changes in type II receptors were observed after IL-1 or IL-6 administration. In contrast, hippocampal type II receptors were dramatically decreased after the injection of TNF. The TNF-induced downregulation of type II receptors was secondary to a marked decrease in the affinity of the receptors (Kd increased 7.2-fold), accompanied by a 51% decrease in receptor number (Bmax). These results emphasize the important role played by TNF in the modulation of the hypothalamic-pituitary-adrenal axis during immune/inflammatory processes and extend the central sites of action of this cytokine to the corticosteroid receptors of the hippocampus.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Nov 1, 1988
Possible modulatory effects of psychoneurogenic stress and endotoxin-induced immune activation on... more Possible modulatory effects of psychoneurogenic stress and endotoxin-induced immune activation on the in vitro corticosterone-releasing effects of lymphokine-containing supernatants (LCS) and adrenocorticotropic hormone (ACTH) were studied in rats. We have found that activation of the immune system by endotoxin increases the in vitro sensitivity of the adrenocortical cells to LCS and ACTH. In addition, we found that psychoneurogenic stress not only produced an increase of in vitro adrenal sensitivity to ACTH, but it also enhanced the release of corticosterone after perfusion of LCS. A synergistic interaction between ACTH and LCS was observed in all experimental groups of animals studied. An increased adrenal sensitivity to LCS and ACTH after stress or immune activation might have a functional significance, since the adrenal cortex is a major site in the response of the organism to alterations in the homeostatic balance. On the other hand, the temporal pattern of in vitro corticosterone release after LCS was different in all groups under study compared with that observed after ACTH challenge. LCS elicited a more rapid corticosterone response that lasted for a shorter time than after giving ACTH. These latter results suggest that different mechanisms may underlie the effects of LCS and ACTH on adrenal corticosteroidogenesis. In conclusion, the present findings further reinforce the existence of possible physiologically relevant interactions between the immune system and the pituitary-adrenal axis.
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Papers by Jose Borrell